Structural basis of West Nile virus neutralization by a therapeutic antibody. Export

@article{citeulike:334268, abstract = {West Nile virus is a mosquito-borne flavivirus closely related to the human epidemic-causing dengue, yellow fever and Japanese encephalitis viruses. In establishing infection these icosahedral viruses undergo endosomal membrane fusion catalysed by envelope glycoprotein rearrangement of the putative receptor-binding domain III (DIII) and exposure of the hydrophobic fusion loop. Humoral immunity has an essential protective function early in the course of West Nile virus infection. Here, we investigate the mechanism of neutralization by the E16 monoclonal antibody that specifically binds DIII. Structurally, the E16 antibody Fab fragment engages 16 residues positioned on four loops of DIII, a consensus neutralizing epitope sequence conserved in West Nile virus and distinct in other flaviviruses. The E16 epitope protrudes from the surface of mature virions in three distinct environments, and docking studies predict Fab binding will leave five-fold clustered epitopes exposed. We also show that E16 inhibits infection primarily at a step after viral attachment, potentially by blocking envelope glycoprotein conformational changes. Collectively, our results suggest that a vaccine strategy targeting the dominant DIII epitope may elicit safe and effective immune responses against flaviviral diseases.}, author = {Nybakken, Grant E. and Oliphant, Theodore and Johnson, Syd and Burke, Stephen and Diamond, Michael S. and Fremont, Daved H.}, citeulike-article-id = {334268}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nature03956}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature03956}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16193056}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16193056}, comment = {Ab neutralisation by preventing conformational changes in Env required for fusion.}, day = {29}, doi = {10.1038/nature03956}, issn = {1476-4687}, journal = {Nature}, keywords = {flavivirus, neutralisation, virus}, month = {September}, number = {7059}, pages = {764--769}, posted-at = {2005-10-04 16:55:42}, priority = {0}, publisher = {Nature Publishing Group}, title = {Structural basis of West Nile virus neutralization by a therapeutic antibody.}, url = {http://dx.doi.org/10.1038/nature03956}, volume = {437}, year = {2005} }

TY - JOUR ID - citeulike:334268 L3 - citeulike-article-id:334268 N2 - West Nile virus is a mosquito-borne flavivirus closely related to the human epidemic-causing dengue, yellow fever and Japanese encephalitis viruses. In establishing infection these icosahedral viruses undergo endosomal membrane fusion catalysed by envelope glycoprotein rearrangement of the putative receptor-binding domain III (DIII) and exposure of the hydrophobic fusion loop. Humoral immunity has an essential protective function early in the course of West Nile virus infection. Here, we investigate the mechanism of neutralization by the E16 monoclonal antibody that specifically binds DIII. Structurally, the E16 antibody Fab fragment engages 16 residues positioned on four loops of DIII, a consensus neutralizing epitope sequence conserved in West Nile virus and distinct in other flaviviruses. The E16 epitope protrudes from the surface of mature virions in three distinct environments, and docking studies predict Fab binding will leave five-fold clustered epitopes exposed. We also show that E16 inhibits infection primarily at a step after viral attachment, potentially by blocking envelope glycoprotein conformational changes. Collectively, our results suggest that a vaccine strategy targeting the dominant DIII epitope may elicit safe and effective immune responses against flaviviral diseases. IS - 7059 JF - Nature SN - 1476-4687 EP - 769 TI - Structural basis of West Nile virus neutralization by a therapeutic antibody. PB - Nature Publishing Group VL - 437 SP - 764 KW - flavivirus KW - neutralisation KW - virus N1 - Ab neutralisation by preventing conformational changes in Env required for fusion. AU - Nybakken, Grant AU - Oliphant, Theodore AU - Johnson, Syd AU - Burke, Stephen AU - Diamond, Michael AU - Fremont, Daved PY - 2005/09/29/ UR - http://dx.doi.org/10.1038/nature03956 ER -